bims-midomi 2026-02-15 papers

Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdaf259

Pharmacokinetic-pharmacodynamic-efficacy modeling of the MDM2 inhibitor brigimadlin in glioblastoma patient-derived xenografts.

Background: Murine double minute 2 (MDM2) inhibitors reactivate wild-type p53 and are a promising therapy for glioblastoma, IDH-wildtype (GBM). Brigimadlin is a highly potent MDM2 inhibitor being tested in a phase 0/1 clinical trial in combination with radiation in GBM.
Methods: Brigimadlin pharmacokinetics, pharmacodynamics, and efficacy were evaluated in GBM patient-derived xenografts (PDXs).
Results: In vitro, brigimadlin impaired viability in TP53 wild-type GBM with an IC50 of 0.8-6.6 nmol/L, but sensitivity did not correlate with MDM2 amplification. In vivo, MDM2 amplification was highly correlated with efficacy. In subcutaneous PDXs, 1 or 2 mg/kg brigimadlin dosed weekly was highly effective in 2 MDM2-amplified PDXs. At 2 mg/kg, brigimadlin delayed tumor regrowth by >5-fold in the MDM2-amplified PDXs compared to 1.5-fold in a non-amplified PDX. In orthotopic PDXs, efficacy was more limited, but 2 mg/kg brigimadlin enhanced the response to fractionated radiation in MDM2-amplified PDXs. Consistent with blood-brain barrier efflux limiting drug distribution, 2 mg/kg brigimadlin extended survival by >5-fold in an MDM2-amplified orthotopic PDX established in Rag1-/-Abcb1a-/- Abcg2-/- mice. In pharmacodynamic studies, p53 target genes were upregulated at both subtherapeutic and therapeutic dose levels, and the extent of activation did not correlate with MDM2 status. Concentrations of brigimadlin in tumor tissue were approximately 10-fold higher in MDM2-amplified tumors, and intracellular drug levels directly correlated with drug-dependent MDM2 upregulation, suggesting target binding affects drug accumulation.
Conclusions: Brigimadlin is highly effective in MDM2-amplified GBM when adequate drug levels are achieved in tumor tissue. MDM2 amplification impacts both treatment efficacy and intratumoral drug accumulation.

Keywords: MDM2; brigimadlin; drug delivery; glioblastoma; p53

DOI: https://doi.org/10.1093/noajnl/vdaf259

Oncol Rev. 2025 ;19 1740261

Ribosome biogenesis rate, a parameter of sensitivity to chemotherapeutic drugs inhibiting rRNA synthesis.

Davide Treré, Lorenzo Montanaro, Massimo Derenzini, Claudio Agostinelli, Enrico Derenzini.

Many drugs currently used in cancer chemotherapy exert their toxic action mainly by inhibiting ribosome biogenesis (RiBi). This is due to the fact that after inhibition of rRNA transcription ribosomal proteins, no longer used for ribosome building, bind to and neutralize the activity of the murine double minute 2 protein (MDM2, HMD2 in humans), thus hindering cell proliferation and possibly inducing apoptotic cell death. Here, we discuss the existing literature showing how RiBi rate and genomic alterations of ribosomal proteins (RP mutations/deletions) influence the degree of MDM2 inhibition after treatment with RiBi inhibitors in cancer cells. There is evidence that a high RiBi rate is associated with a high RPs release with strong inhibition of MDM2 activity and consequent induction of apoptotic cell death in response to RiBi inhibitors, whereas a low RiBi rate or RP mutations/deletions are associated with a degree of MDM2 inhibition insufficient to kill cancer cells. In the latter case, in cells with wild type p53, association with drugs which stabilize p53 with different mechanisms may overcome cancer cells resistance to RiBi inhibition, whereas in cancers lacking functional p53 addition of MDM2 inhibitors should be considered. From this, the necessity to evaluate the rate of ribosome biogenesis together with the presence of RP mutations/deletions in cancer tissues for predicting the sensitivity of cancer cells to RiBi inhibitors in order to choose more appropriate therapeutic protocols.

Keywords: MDM2; cancer; chemotherapy; p53; rRNA synthesis; ribosomal proteins; ribosome biogenesis

DOI: https://doi.org/10.3389/or.2025.1740261

Pathol Res Pract. 2026 Jan 20. pii: S0344-0338(26)00026-9. [Epub ahead of print]280 156375

KLF11 interacts with MDM2 to stabilize E2F1 and promotes DNA damage repair to induce radioresistance in esophageal cancer cells.

Yaoxiong Xia, Jiazhu Wang, Dongmei Zhao, Yanli Li, Songqin Li, Man Li, Renyi Dong, Li Wang.

OBJECTIVE: This study aimed to investigate the function of KLF11 in regulating radiosensitivity (RT) in esophageal squamous cell carcinoma (ESCC) and to elucidate the underlying mechanisms.
METHODS: A nude mouse ESCC xenograft model was established by injecting KYSE150 cells into the left dorsal flank. Cell proliferation was assessed using cell counting kit-8 (CCK-8) and colony formation assays, while DNA damage was evaluated via a neutral comet assay. Key gene and protein expression levels were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry. Additionally, coimmunoprecipitation and immunofluorescence were employed to validate proteinprotein interactions.
RESULTS: KLF11 expression was upregulated in both ESCC and RT-resistant tissues. At the cellular level, KLF11 expression was higher in ESCC cell lines than in the normal esophageal epithelial cell line HET-1A, with the most pronounced upregulation in KYSE150 cells and the least in TE1 cells. Notably, KLF11 knockdown under ionizing radiation exposure suppressed proliferation and colony formation, promoted apoptosis, and increased the expression of the DNA damage marker γ-H2AX as well as overall DNA damage levels in KYSE150 cells. Conversely, KLF11 overexpression in TE1 cells led to the opposite phenotype, suggesting that KLF11 confers RT resistance in ESCC by mitigating DNA damage. Further investigations revealed that KLF11 primarily repairs RT-induced DNA damage through the homologous recombination (HR) pathway rather than through nonhomologous end joining (NHEJ). Additionally, the expression of MDM2, E2F1, and RAD51 was significantly elevated in ESCC and RT-resistant ESCC tissues. Mechanistically, KLF11 promotes MDM2 expression, which inhibits E2F1 ubiquitination, thereby stabilizing E2F1 protein levels and enhancing RAD51-mediated HR repair, ultimately leading to RT resistance in ESCC.
CONCLUSION: This study elucidates the critical role and molecular mechanism through which KLF11 drives radiotherapy resistance in ESCC by regulating the MDM2/E2F1 axis and enhancing HR repair, thereby providing a solid theoretical foundation and potential target for the development of KLF11-targeted radiosensitization therapies for ESCC.

Keywords: DNA damage repair; E2F1; Esophageal squamous cell carcinoma; KLF11; MDM2; Radiotherapy resistance

DOI: https://doi.org/10.1016/j.prp.2026.156375